Some of the most dreadful epidemics, inherited diseases and cancerous infections in the history of mankind are afflicting the world's people at a rapid and discomforting rate. These maladies are being caused in many instances by the increasing cases of cancer, of viral infections, such as human immunodeficiency viruses (HIV) or HTLV and of severe beta-chain hemoglobinopathies. When one pauses to reflect upon the devastating pain, suffering and ultimately death experienced by persons afflicted, these moments of reflection underscore the tremendous importance which must be accorded medical research. In response to the need to alleviate suffering and add comfort to human life, the scientific community throught the world is searching for effective treatments to prevent or ameliorate diseases.
In order to present the enormous scope of this unitary invention in a comprehensive form while preserving the essential need for clarity in presentment, this invention focusing on phenylacetate and its derivatives will be described in the following three (3) subsections, designated herein as A. Phenylacetate In Cancer prevention and maintenance therapy; B. Phenylacetate and its derivatives in the Treatment and Prevention of AIDS; and C. Induction of fetal hemoglobin synthesis in .beta.-chain hemoglobinopathies by phenylacetate and its derivatives.
Description of related disclosures
Phenylacetic acid (PAA) is a protein decomposition product found throughout the phylogenetic spectrum, ranging from bacteria to man. Highly conserved in evolution, PAA may play a fundamental role in growth control and differentiation. In plants, PAA serves as a growth hormone (auxin) promoting cell proliferation and enlargement at low doses (10-5-10-7 M), while inhibiting growth at higher concentrations. The effect on animal and human cells is less well characterized. In humans, PAA acid is known to conjugate glutamine with subsequent renal excretion of phenylacetylglutamine (PAG). The latter, leading to waste nitrogen excretion, has been the basis for using PAA or preferably its salt sodium phenylacetate (NaPA) in the treatment of hyperammonemia associated with inborn errors of ureagenesis. Clinical experience indicates that acute or long-term treatment with high NaPa doses is well tolerated, essentially free of adverse effects, and effective in removing excess glutamine. Brusilow, S. W., Horwich, A. L. Urea cycle enzymes. Metabolic Basis of Inherited Diseases, Vol. 6:629-633 (1989)!. These characteristics should be of value in cancer intervention, treatments to inhibit virus replication and treatment of severe beta-chain hemoglobinopathies.
Glutamine is the major nitrogen source for nucleic acid and protein synthesis, and substrate for energy in rapidly dividing normal and tumor cells. Compared with normal tissues, most tumors, due to decreased synthesis of glutamine along with accelerated utilization and catabolism, operate at limiting levels of glutamine availability, and consequently are sensitive to further glutamine depletion. Considering the imbalance in glutamine metabolism in tumor cells and the ability of PAA to remove glutamine, PAA has been proposed as a potential antitumor agent, however, no data was provided to substantiate this proposal. Neish, W. J. P. "Phenylacetic Acid as a Potential Therapeutic Agent for the Treatment of Human Cancer", Experentia, Vol. 27, pp. 860-861 (1971)!.
Despite efforts to fight cancer, many malignant diseases that are of interest in this application still present a major challenge to clinical oncology. Prostate cancer, for example, is the second most common cause of cancer deaths in men. Current treatment protocols rely primarily on hormonal manipulations, however, in spite of initial high response rates, patients often develop hormone-refractory tumors, leading to rapid disease progression with poor prognosis. Overall, the results of cytotoxic chemotherapy have been disappointing, indicating a long felt need for new approaches to treatment of advanced prostatic cancer. Other diseases resulting from abnormal cell replication for example, metastatic melanomas, brain tumors of glial origin (e.g., astrocytomas), and lung adenocarcinoma, are all highly aggressive malignancies with poor prognosis. The incidence of melanoma and lung adenocarcinoma has been increasing significantly in recent years. Surgical treatment of brain tumors often fails to remove all tumor tissues, resulting in recurrences. Systemic chemotherapy is hindered by blood barriers. Therefore there is an urgent need for new approaches to the treatment of human malignancies such as advanced prostatic cancer, melanoma, brain tumors, and others.
The development of the methods of the present invention was guided by the hypothesis that metabolic traits that distinguish tumors from normal cells could potentially serve as targets for therapeutic intervention. Tumor cells show unique requirements for specific amino acids, of which glutamine would be the desired choice because of its major contribution to energy metabolism and to synthesis of purines, pyrimidines, and proteins. Along this line, promising antineoplastic activities have been demonstrated with glutamine-depleting enzymes such as glutaminase, and various glutamine antimetabolites, unfortunately, the clinical usefulness of these drugs has been limited by unacceptable toxicities. Consequently, the present invention focuses on PAA, a plasma component known to conjugate glutamine in vivo.
In addition to its effect on glutamine phenylacetate can induce tumor cells to undergo differentiation. (See examples 1-5, 8 and 9 herein) Differentiation therapy is a known desirable approach to cancer intervention. The underlying hypothesis is that neoplastic transformation results from defects in cellular differentiation. Inducing tumor cells to differentiate would prevent tumor progression and bring about reversal of malignancy. Several differentiation agents are known, but their clinical applications have been hindered by unacceptable toxicities and/or deleterious side effects.
Accordingly, a major object of the present invention is to provide a method for treating various cancerous conditions with PAA and its pharmaceutically acceptable salts and derivatives.
Another object of the present invention is to provide a method for the prevention of tumor progression and the development of malignant conditions in high risk individuals by administering prophylactically effective amounts of nontoxic agents such as phenylacetate and its pharmaceutically acceptable derivatives.
Another object of the present invention is to provide a method for the amelioration of and prophlactic treatment against viral infections. Still another object of the present invention is to provide a method for the amelioration of and prophylactic treatment against severe anemia associated with beta-chain hemoglobinopathies.
It is yet a further object to provide a method of treating or preventing the onset of malignancies, viral infections associated with AIDS or severe beta-chain hemoglobinopathies with a combination of Phenylacetate (or its pharmaceutically acceptable derivatives) and various other therapeutic or preventive agents alone or in conjunction with conventional therapies.
A further object of the invention is to provide effective pharmaceutical formulations of PAA and its pharmaceutically acceptable derivatives for carrying out the above methods.